tbuckley/cabot-search huggingface dataset:
Abstract 5763: Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer
Authors: Xiaolong Cui, Aigang Ren, Hao Chen, Yaoliang Huo, Yanwu Zeng, Hao Zhang, Meizhen Hu, He Huang, Yuntong Guo
Journal: Cancer Research (2022)

Abstract Background: Colorectal cancer (CRC) is a malignant tumor that seriously threatens human health. Valuable diagnostic and prognostic biomarkers are urgently needed for colorectal cancer. We aim to analyze the mutational characteristics of Chinese CRC patients with different tumor differentiation degree, in order to improve the diagnosis and prognosis of this population. Methods: We retrospectively analyzed tumor tissue specimens from colorectal cancer patients who were treated at the First Affiliated Hospital of Shanxi Medical University from 2019 to 2021. Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: There were 35 males (55.6%) and 28 females (44.4%) with a median age of 60 (range 23-87) years were involved, including 55 moderately and well differentiated and 8 poorly differentiated colorectal tumors. The mutational frequency of BRAF in the poorly differentiated group was significantly higher than that in moderately and well differentiated group(25% vs. 1.8%, p=0.04). The mutational frequencies of the chromosome folding pathway, notch pathway, and PI3K pathway in poorly differentiated group were significantly lower than that in moderately and well differentiated group(p=0.975X10-15,p=0.97 X 10-26,and p=0.00517, respectively). In this study, the mutations of PDCD1 (programmed cell death 1) and TSC2 Significantly associated with tumor mutation burden (p=0.007 and p=0.047, respectively). In addition, high-frequency co-mutations of chromosome folding-related genes and DNA damage repair-related genes, such as co-mutations between ARID1A-MLH1,KMT2D-MSH6,KMT2D-MSH2, KMT2D-BRCA1, ARID1A-CHEK2, were detected in this study. Conclusions: We compared the genomic alterations between well-differentiated group and poorly-differentiated group in Chinese CRC patients. Our data showed significant differences in mutational frequency of chromosome folding pathways, notch pathways, and PI3K pathways between well-differentiated group and poorly-differentiated group. Meanwhile, we also identified the high-frequency and complex co-mutation characteristics of chromosome folding pathway genes and DNA damage repair genes in Chinese CRC patients. Citation Format: Xiaolong Cui, Aigang Ren, Hao Chen, Yaoliang Huo, Yanwu Zeng, Hao Zhang, Meizhen Hu, He Huang, Yuntong Guo. Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5763.
Abstract 5546: Inflamed lymph nodes mark active tumor immune response in colorectal cancer patients
Authors: Dingcheng Shen, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu
Journal: Cancer Research (2022)

Abstract Background Tumor-infiltrating lymphocytes (TILs) can be used to predict immune response in multiple tumors. Currently, the evaluation of TILs relies on pathological and molecular examine on resected tumor samples. Enlarged regional lymph nodes could be attributed to tumor involvement or local inflammation with active immune response. We therefore aimed to investigate the role of inflamed lymph nodes in distinguishing the hot tumor from cold tumor. Methods Fresh-frozen tumor samples from pathologically-confirmed node-negative colorectal cancer patients with inflamed nodes (n= 22) and non-inflamed nodes (n= 23) were used to generate the genome-wide DNA methylation profile using Infinium Methylation EPIC BeadChip. The inflamed and non-inflamed nodes were defined as the pathologically-confirmed negative regional lymph nodes with enlarged size (≥ 5mm) and normal size (&amp;lt; 5mm) in radiological imaging, respectively. A MeTIL algorithm that integrates CD3+ T cell-specific differentially methylated positions was constructed and validated by immunohistochemical assay to evaluate TIL-based tumor immune response in bulk tumor samples. Results The baseline characteristics were balanced between patients with inflamed and non-inflamed nodes. The high abundance of TILs was significantly associated with inflamed nodes (P= 0.025). In addition, we identified a subgroup of superhot tumors characterized by inflamed nodes, enriched TILs and favorable overall survival outcomes (HR 0.53, 95% CI: 0.36-0.97; P = 0.032). Conclusions Inflamed regional lymph nodes in radiological imaging indicate potential active immune response in tumor. Our findings provide an easily accessible biomarker for cancer immunotherapy. Citation Format: Dingcheng Shen, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Inflamed lymph nodes mark active tumor immune response in colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5546.
Abstract 2838: Antigen-independent expansion enhances efficacy of CAR-T cells against solid tumor
Authors: Zhiyuan Cao, Chengfei Pu, Xianyang Jiang, Guiting Han, Yuzhe Peng, Wensheng Wang, Wei Ding, Xiaogang Shen, Dongqi chen, Beibei Jia, Xiaoqiang Xu, Zhipeng Huang, Xi Huang, Wenbi Liu, Ruihong Zhu, Lee Tian, Christopher Ballas, Victor.X Lu, Zhao Wu, Lei Xiao
Journal: Cancer Research (2022)

Abstract One key hurdle for the CAR-T cell treatment of solid tumors is the limited accessibility of solid tumor antigens outside the tumor microenvironment, which prohibits the expansion of solid tumor-targeting CAR-T cells in patients. Here, we report the characterization of prostatic acid phosphatase (PAP) as a feasible CAR-T target for prostate cancer and a novel approach, named CoupledCAR, to expand solid tumor-targeting CAR-T cells lacking solid tumor antigens based on the observation of non-transduced T cells proliferating together with CD19 CAR-T cells during the treatment of acute lymphocyte leukemia. We demonstrated that CoupledCAR can significantly enhance the expansion and antitumor efficacy of PAP CAR-T cells both in vitro and in vivo. Furthermore, we showed that the expansion of solid tumor-targeting CAR-T cells does not depend on CAR/CD3ζ stimulation through direct antigen binding with CAR but enhances the memory status of CAR-T cells and causes little exhaustion. Since the CoupledCAR system does not rely on solid tumor antigens, we propose that it can be utilized in all CAR-T and T cell therapies for the treatment of solid tumors. Citation Format: Zhiyuan Cao, Chengfei Pu, Xianyang Jiang, Guiting Han, Yuzhe Peng, Wensheng Wang, Wei Ding, Xiaogang Shen, Dongqi chen, Beibei Jia, Xiaoqiang Xu, Zhipeng Huang, Xi Huang, Wenbi Liu, Ruihong Zhu, Lee Tian, Christopher Ballas, Victor.X Lu, Zhao Wu, Lei Xiao. Antigen-independent expansion enhances efficacy of CAR-T cells against solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2838.
Abstract 1285: Chemotherapy induces PD-L1 overexpression in CRC through NF-κBp65
Authors: Fan Fan, Susmita Ghosh, Lee Ellis, Rajat Bhattacharya
Journal: Cancer Research (2022)

Abstract Background: The programmed cell death ligand (PD-L1) is an immune-inhibitory molecule that suppresses the activation of T cells, leading to the survival and growth of tumors. Overexpression of PD-L1 on cancer cells is associated with poor clinical outcomes in many types of cancers. PD-L1 upregulation contributes to chemoresistance in several types of cancer, but little is known about the mechanisms for alterations in PD-L1 expression associated with chemotherapy, especially in patients with CRC. Therefore, a better understanding of the mechanisms underlying changes in PD-L1 levels in response to standard of care chemotherapeutics in CRC is important. In this study, we examined the effects of thechemotherapeutics that are approved for the treatment of patients with CRC (oxaliplatin, 5FU, and irinotecan whose metabolite is SN38) in inducing PD-L1 expression and determining the molecular pathwaysinvolved in PD-L1 regulation. Methods: PD-L1 expression in CRC cell lines was determined in vitro using western blotting and FACS analysis. Changes in PD-L1 transcript levels were measured using real time PCR. RPPA analyses were performed to identify proteins/pathways affected by chemotherapeutics. Pharmacological inhibitors and siRNAs were used to target specific proteins in determining their role in PD-L1 expression. Results: We observed that oxaliplatin, 5FU, and SN38, resulted in induction of PD-L1 to various degrees. Interestingly this induction was observed in KRAS or BRAF mutated CRC cells but not in CRC cells with wild-type KRAS and BRAF. Increased levels of PD-L1 were due to increased transcription of PD-L1 resulting from exposure to chemotherapeutics. Chemotherapeutics lead to the activation of the DNA damage signaling mediator Chk1 and the downstream transcription activator NF-κBp65. Inhibition of Chk1 or NF-κBp65 resulted in abrogated PD-L1 induction in response to chemotherapeutic treatment. Conclusion: PD-L1 can be induced following treatment with chemotherapy in CRC cells harboring mutations in BRAF or KRAS. Our findings provide a rationale for studies combining inhibitors of NF-κBp65 with standard of care chemotherapeutics in CRC to block PD-L1 expression and enhance the efficacy of chemotherapy damaged-tumor cell clearance by innate immunity that, in turn, should improve patient outcomes. Citation Format: Fan Fan, Susmita Ghosh, Lee Ellis, Rajat Bhattacharya. Chemotherapy induces PD-L1 overexpression in CRC through NF-κBp65 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1285.
Abstract 184: High-throughput chemotherapeutic drug screening of tumor spheroids with individual spheroid results using image cytometry
Authors: Jordan Bell, Shilpaa Mukundan, Matthew Teryek, Bo Lin, Biju Parekkadan, Leo Chan
Journal: Cancer Research (2022)

Abstract Three-dimensional cancer models have gained popularity for in vitro studies of chemotherapeutic compounds by providing a more physiologically relevant analog of gas, nutrient, and drug diffusion throughout the tumor microenvironment. Some 3D assays are performed to study individual spheroids over time, where a majority of these assays rely on maintaining a single spheroid in each well of a 96-well round-bottom ultra-low attachment plate, limiting the number of spheroids in a study. Other assays may gather population-level data from large ensembles of spheroids grown together, but the information about individual differences amongst the spheroids is lost. Important kinetic information may also be lost for destructive endpoint assays such as MTS or MTT. Here, we describe the development of a 3D image cytometry assay that is capable of generating kinetic data for thousands of breast cancer spheroids at the individual level. T47D spheroids are grown and maintained in a 24-well Aggrewell࣪400 plate and imaged using the Celigo image cytometer. Each well contains more than 1000 subwells that both aid in spheroid formation and constrain each spheroid to a specific location. Using the spheroid location data, we are able to track and monitor the growth of each spheroid over 7 days. Furthermore, we investigate the dose-dependent effects on spheroid viability of 6 anti-cancer drugs (Doxorubicin, Everolimus, Gemcitabine, Metformin, Paclitaxel and Tamoxifen) using calcein AM and propidium iodide (PI). To validate the viability measurement results, we utilize the CellTiter96® MTS assay as an orthogonal method to compare the dose-dependent trends using both the calcein AM and PI fluorescence intensities as well as the spheroid sizes. This work may lay a foundation for the investigation of other spheroids, organoids, or tissue samples, significantly increasing the number of spheroids analyzed per condition, improving the statistical analysis, and adding more parameters to further analyze the spheroids. These improvements may be especially helpful for spheroids grown from patient-derived or otherwise heterogeneous cell populations Citation Format: Jordan Bell, Shilpaa Mukundan, Matthew Teryek, Bo Lin, Biju Parekkadan, Leo Chan. High-throughput chemotherapeutic drug screening of tumor spheroids with individual spheroid results using image cytometry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 184.
Abstract 5585: Inhibition of CSF1R enhances the antitumor efficacy of DC derived exosomes by modulating immunosuppressive tumor microenvironment
Authors: Anjali Barnwal, Jayanta Bhattacharyya, Bushra Ateeq
Journal: Cancer Research (2022)

Abstract Dendritic cell (DC) derived exosomes (Dex) provide many advantages over DC vaccines such as cost effectiveness, stability, sensitivity to the systemic microenvironment. Though, Dex showed better therapeutic outcome in murine models, however, desired outcome was not achieved in clinical trials as it failed to induce robust immunity to modulate the immunosuppressive tumor microenvironment (TME). Colony stimulating factor-1 (CSF-1) binds to its receptor (CSF-1R) and recruits tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) in the TME which eventually creates the tumor immunosuppressive. Hence, in this study we used PLX-3397, a small molecule inhibitor of CSF-1R to enhance the antitumor efficacy of Dex. In a syngenic B16-F10murine melanoma model, we found that the combination treatment delayed the tumor growth and improved the survival compare to the mono therapy. In TME, the combination treatment significantly depleted the TAMs and MDSCs and increased the infiltration of lymphocytes (TILs). Additionally, Th1 population were found significantly higher in tumor as well as in spleen with mice received both Dex and PLX3397. In conclusion, PLX-3397 enhanced the in vivo antitumor efficacy of Dex by modulating the immunosuppressive microenvironment in tumor. Citation Format: Anjali Barnwal, Jayanta Bhattacharyya, Bushra Ateeq. Inhibition of CSF1R enhances the antitumor efficacy of DC derived exosomes by modulating immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5585.
Abstract 109: The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation
Authors: Marion Morel, Weiwen Long
Journal: Cancer Research (2022)

Abstract F-box proteins are essential components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases in that they bind to SKP1 through the F-box motif and bring the substrate to the E3 ligase complex for ubiquitination. FBXL16 is a poorly studied F-box protein. FBXL16 doesn’t interact with Cul1 and might not form a functional SCF-E3 ligase complex. Unexpectedly, we recently found that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, such as SRC-3 and c-myc, by antagonizing the activity of another F-box protein, FBW7. By data mining, we found that FBXL16 is highly upregulated in many cancers, including lung adenocarcinomas (LUADs), and its upregulation is associated with poor overall survival. LUAD is the most common form of lung cancer, and about 30% of LUADs harbor constitutively active oncogenic KRAS mutants. However, currently no drug is available for effectively treating LUADs expressing KRAS mutants. Hence, there is an unmet need to identify new therapeutic targets. Here, we report that FBXL16 protein level is selectively upregulated and is strongly correlated with insulin receptor substrate-1 (IRS1) protein expression in LUAD cell lines with activating KRAS mutations. By cycloheximide treatment, we found that FBXL16 greatly increases IRS-1 protein stability and level, leading to upregulation of IGF-1 (Insulin)/IRS1/PI3K Akt signaling. Importantly, the upregulation of IRS1 protein and its signaling by FBXL16 was confirmed in mouse lungs with conditional overexpression of FBXL16 transgene. Moreover, depletion of FBXL16 by RNA interference inhibits IGF-1-induced lung cancer cell proliferation and migration. Taken together, our findings reveal FBXL16 as a potential target for treating LUADs with KRAS activating mutations. Citation Format: Marion Morel, Weiwen Long. The F-box protein FBXL16 upregulates IRS1 signaling in lung adenocarcinomas with KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 109.
Abstract 3102: MiniPDX and omics analysis for clinical indication and biomarker identification
Authors: Shuai Wang, Yu Di, Rongyu Li, Yang Liu, Xiaorong Gu, Kaimeng Hu, Danyi Wen
Journal: Cancer Research (2022)

Abstract MiniPDX as an in vivo version of the organoid assay represents a novel platform of fast turnaround (7 days) in vivo drug sensitivity test, using either fresh patient tumor samples or tissues from established PDX models. We systematically evaluated and compared the response rates of MiniPDX assays and PDX assays pair-wise in 26 PDX models involving 3 types of cancers to 12 clinical relevant regimens, and found a high correlation between drug responses between the two assays, with sensitivity and specificity of 80% and 93%, respectively. LIDE has completed over 2,400 MiniPDX assays for precision medicine in clinical, including over 50 indications. Using MiniPDX for ranking the drug/treatment approved in clinical practice facilitates prioritization of the best strategy for benefiting patient in precision medicine, while screening a series of small/large molecules within the similar scaffold enables selection of the best candidate for further drug R&amp;D. Importantly, performing MiniPDX Mouse Trial using fresh tumor samples generated from clinic is beneficial for determination of potential clinical indication that would be fit for the investigating new drug. RNA or DNA can be extracted and enriched from only thousands of cells left from MiniPDX preparation by K cell technology, while RNAseq can be further analyzed via functional genomic imaging (FGI). The Omics data would be useful for determination of potential biomarkers to distinguish responders vs non-responders in population with certain indication(s) and further application in patient stratification to confirm inclusive/exclusive criteria in clinical trials. Citation Format: Shuai Wang, Yu Di, Rongyu Li, Yang Liu, Xiaorong Gu, Kaimeng Hu, Danyi Wen. MiniPDX and omics analysis for clinical indication and biomarker identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3102.
Abstract 2681: Novel and selective inhibitors of KRASG12D
Authors: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar
Journal: Cancer Research (2022)

Abstract RAS proteins are family of small GTP-binding proteins that play a major role in regulating cellular responses such as proliferation, differentiation, migration, and cell growth. RAS proteins function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states, which relay cellular signals in response to extracellular stimuli. Aberrant RAS signaling plays a role in up to 30% of all human cancers, with the highest incidence occurring in carcinomas of the pancreas (63–90%), colon (36–50%), and lung (19–30%). Targeting the inactive, GDP bound KRASG12C has been a promising approach for generating novel anti RAS therapies, which is validated by the approval of AMG 510 (Lumakras) by the FDA. It is also known that KRASG12D also retains GTPase activity. Consequently, KRASG12D is one of the most important chemotherapeutic drug targets. KRASG12D is commonly observed in pancreatic cancer. Here we describe preclinical profile of a potent, selective, in-vivo tool compound, VRTX144. VRTX144 was potent in HPAC cell line, representing pancreatic adenocarcinoma, and a panel of KRASG12D mutated cell lines. It was found to be several folds less active in non-KRASG12D mutant cell lines. In vitro combination strategies with other targeted therapies such as EGFR, SHP2 and CDK4/6 inhibitor is also being investigated. VRTX144 exhibited low propensity for metabolism in microsomes, and has high protein bound. VRTX144 was found to have no adverse effect in hERG upto 10 uM. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Mahesh Mohan Shidore, Anuj Ramesh Kshirsagar. Novel and selective inhibitors of KRASG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2681.
Abstract SY17-03: Reimagining druggability using chemoproteomic platforms
Authors: Daniel K. Nomura
Journal: Cancer Research (2022)

Abstract The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel ligandable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Our second research area focuses on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to develop new induced proximity-based therapeutic modalities. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery. Citation Format: Daniel K. Nomura. Reimagining druggability using chemoproteomic platforms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY17-03.